Study of Safety and Efficacy of Alpelisib With Everolimus or Alpelisib With Everolimus and Exemestane in Advanced Breast Cancer Patients, Renal Cell Cancer and Pancreatic Tumors

This study is currently recruiting participants. (see Contacts and Locations)
Verified January 2016 by Novartis
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT02077933
First received: February 28, 2014
Last updated: January 20, 2016
Last verified: January 2016
  Purpose

Dose escalation part: to determine the highest dose of alpelisib administered on a daily basis when given in combination with daily everolimus or in combination with daily everolimus and exemestane.

Dose expansion part: To describe safety and tolerability of the alpelisib and everolimus or alpelisib, everolimus and exemestane combinations.


Condition Intervention Phase
Neoplasms,
Breast Neoplasms,
Kidney Neoplasms,
Pancreatic Neuroendocine Neoplasms
Drug: alpelisib
Drug: everolimus
Drug: exemestane
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase Ib Dose-finding Study of BYL719 Plus Everolimus and BYL719 Plus Everolimus Plus Exemestane in Patients With Advanced Solid Tumors, With Dose-expansion Cohorts in Renal Cell Cancer (RCC), Pancreatic Neuroendocrine Tumors (pNETs), and Advanced Breast Cancer (BC) Patients.

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Dose escalation : Incidence of dose Limiting Toxicity (DLTs) [ Time Frame: First 35 days of treatment ] [ Designated as safety issue: Yes ]

    To determine the MTD and/or RDE of alpelisib in combination with everolimus, and the MTD and/or RDE of alpelisib in combination with everolimus and exemestane.

    A dose-limiting toxicity (DLT) is an adverse event or abnormal laboratory value assessed as being unrelated to disease, disease progression, inter-current illness, or concomitant medications, and that occurs within the first 35 days of treatment with alpelisib plus everolimus or alpelisib plus everolimus plus exemestane and meets any of the pre-defined criteria.


  • Dose expansion: Number of patients with adverse events as a measure of safety and tolerability [ Time Frame: Screening, every 28 days until 30 days after last dose ] [ Designated as safety issue: Yes ]
    Type, intensity, severity and seriousness of adverse events according to the National Cancer Institute Common Terminology Criteria for Advers Events (NCI CTC AE) v4.03. Dose interruptions, reductions and dose intensity


Secondary Outcome Measures:
  • Dose escalation: Number of patients with adverse events as a measure of safety and tolerability [ Time Frame: Screening, every 28 days, until 30 days after last dose ] [ Designated as safety issue: Yes ]
    type, intensity, severity and seriousness of adverse events according to the NCI CTC AE v4.03. Dose interruptions, reductions and dose intensity

  • Dose escalation : alpelisib, everolimus and exemestane (when applicable) Plasma concentrations [ Time Frame: Cycle 1 Day 7, Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 16, Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 2, Cycle 2 Day 15, Day 1 of each subsequent cycle ] [ Designated as safety issue: No ]
    Plasma concentration time profiles of alpelisib , BZG791, everolimus and exemestane (when applicable). Plasma PK parameters of everolimus, alpelisib, BZG791 and exemestane (when applicable)

  • Dose escalation : alpelisib, everolimus drug-drug interaction [ Time Frame: Cycle 1 Day 7, Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 16, Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 2, Cycle 2 Day 15, Day 1 of each subsequent cycle ] [ Designated as safety issue: No ]
    Plasma PK parameters of everolimus including AUC ratio (single agent vs. combination)

  • Dose expansion: Progression free survival (Doublet and triplet cohorts) [ Time Frame: Baseline, every 8 weeks until first documented disease progression up to 2.5 years. ] [ Designated as safety issue: No ]
    Progression-free survival is defined as the time from start date of study treatment until objective tumor progression or death from any cause.

  • Dose expansion : Duration of Response (Doublet and triplet cohorts) [ Time Frame: Baseline, every 8 weeks until first documented disease progressionup to 2.5 years. ] [ Designated as safety issue: No ]
    Duration of response is defined as the time of first occurrence of Complete Response or Partial Response until the date of the first documented disease progression or death due to the disease.

  • Dose expansion: Clinical benefit Rate (Doublet and triplet cohorts) [ Time Frame: Baseline, every 8 weeks until first documented disease progression up to 2.5 years. ] [ Designated as safety issue: No ]
    Clinical benefit rate is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR) or stable disease (SD) for more than 24 weeks.

  • Dose expansion: Overall response rate (Doublet and triplet cohorts) [ Time Frame: Baseline, every 8 weeks until first documented disease progression up to 2.5 years. ] [ Designated as safety issue: No ]
    Overall response rate is defined as the proportion of patients with a best overall response of complete response (CR) or partial response (PR), based on RECIST 1.1 criteria and the investigator assessment.

  • Dose expansion: Progression free survival rate at 16 weeks (Triplet) [ Time Frame: Baseline, up to 16 weeks. ] [ Designated as safety issue: No ]
    Progression-free survival rate at 16 weeks is defined as the proportion of patients who are progression free 16 weeks after the study start reference date


Estimated Enrollment: 166
Study Start Date: May 2014
Estimated Study Completion Date: December 2017
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: alpelisib and everolimus
alpelisib and everolimus administered once a day
Drug: alpelisib

alpelisib is administered orally once a day on a continuous dosing schedule and dosed on a flat-fixed dose and not adjusted by body weight or body surface area, starting on Day 8 of Cycle 1 in the dose escalation and Day 1 of Cycle 1 in the dose expansion.

In the doublet dose escalation, the alpelisib starting dose is 300 mg. The alpelisib dose may be escalated or de-escalated, as needed.

In the triplet dose escalation part, the alpelisib starting dose is one dose level lower of the MTD as determined during the doublet escalation. The alpelisib dose may be escalated or de-escalated, as needed.

In the doublet dose expansion and triplet dose expansion (patients assigned to alpelisib, everolimus and exemestane), alpelisib is administered at the recommended dose determined in the dose escalation.

In the triplet dose expansion (patients assigned to alpelisib and exemestane), alpelisib is administered at a dose of 250 mg daily.

Drug: everolimus

everolimus is administered orally once a day on a continuous dosing schedule and dosed on a flat-fixed dose and not adjusted by body weight or body surface area, starting on Day 1 of cycle 1 in both the dose escalation and dose expansion parts.

In the dose escalation part, the everolimus starting dose is 2,5 mg. In the dose expansion part, everolimus is administered at the recommended dose determined in the dose escalation.

Experimental: alpelisib, everolimus and exemestane
alpelisib, everolimus and exemestane administered once a day
Drug: alpelisib

alpelisib is administered orally once a day on a continuous dosing schedule and dosed on a flat-fixed dose and not adjusted by body weight or body surface area, starting on Day 8 of Cycle 1 in the dose escalation and Day 1 of Cycle 1 in the dose expansion.

In the doublet dose escalation, the alpelisib starting dose is 300 mg. The alpelisib dose may be escalated or de-escalated, as needed.

In the triplet dose escalation part, the alpelisib starting dose is one dose level lower of the MTD as determined during the doublet escalation. The alpelisib dose may be escalated or de-escalated, as needed.

In the doublet dose expansion and triplet dose expansion (patients assigned to alpelisib, everolimus and exemestane), alpelisib is administered at the recommended dose determined in the dose escalation.

In the triplet dose expansion (patients assigned to alpelisib and exemestane), alpelisib is administered at a dose of 250 mg daily.

Drug: everolimus

everolimus is administered orally once a day on a continuous dosing schedule and dosed on a flat-fixed dose and not adjusted by body weight or body surface area, starting on Day 1 of cycle 1 in both the dose escalation and dose expansion parts.

In the dose escalation part, the everolimus starting dose is 2,5 mg. In the dose expansion part, everolimus is administered at the recommended dose determined in the dose escalation.

Drug: exemestane
exemestane is administered orally once a day on a continuous dose of 25 mg starting on Day 1 of Cycle 1 in both the dose escalation and dose expansion.
Experimental: alpelisib and exemestane
alpelisib and exemestane administered once a day
Drug: alpelisib

alpelisib is administered orally once a day on a continuous dosing schedule and dosed on a flat-fixed dose and not adjusted by body weight or body surface area, starting on Day 8 of Cycle 1 in the dose escalation and Day 1 of Cycle 1 in the dose expansion.

In the doublet dose escalation, the alpelisib starting dose is 300 mg. The alpelisib dose may be escalated or de-escalated, as needed.

In the triplet dose escalation part, the alpelisib starting dose is one dose level lower of the MTD as determined during the doublet escalation. The alpelisib dose may be escalated or de-escalated, as needed.

In the doublet dose expansion and triplet dose expansion (patients assigned to alpelisib, everolimus and exemestane), alpelisib is administered at the recommended dose determined in the dose escalation.

In the triplet dose expansion (patients assigned to alpelisib and exemestane), alpelisib is administered at a dose of 250 mg daily.

Drug: exemestane
exemestane is administered orally once a day on a continuous dose of 25 mg starting on Day 1 of Cycle 1 in both the dose escalation and dose expansion.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria For entire trial:

  • Adult > or = 18 years old
  • has signed the Informed Consent Form
  • has tumor tissue available for the analysis as described in the protocol
  • has an Eastern Cooperative Oncology Group performance status ≤2
  • has adequate bone marrow and organ function as defined in the protocol
  • is able to swallow and retain oral medication
  • has either measurable or non-measurable disease as per RECIST 1.1.

Inclusion Criteria for the BYL719+ Everolimus combination - escalation phase - all above plus has a histologically/cytologically confirmed metastatic and/or recurrent solid tumors for whom no standard therapy exists.

Inclusion Criteria for the BYL719+ Everolimus combination - expansion phase, renal cell carcinoma cohort - all of above first 7 criteria plus has an histologically/cytologically confirmed Renal Cell Cancer as detailed in the protocol

Inclusion Criteria for the BYL719+ Everolimus combination - expansion phase, pancreatic NeuroEndocrine Tumor cohort

- all of above first 7 criteria plus has an histologically/cytologically confirmed pancreatic NeuroEndocrine Tumor as detailed in the protocol

Inclusion Criteria for the BYL719+ Everolimus combination - expansion phase, mTOR inhibitor-pretreated patients' cohort - all of above first 7 criteria plus has a histologically and/or cytologically confirmed solid malignancy as described in the protocol

Inclusion Criteria for the breast cancer cohorts in escalation and expansion phases, - all of above first 7 criteria plus is post-menopausal and has a histologically and/or cytologically confirmed diagnosis of breast cancer as described in the protocol

Specific Inclusion Criteria at the time of cross-over (breast cancer, expansion phase),

- Patient randomized to the alpelisib and exemestane combination who has a radiologically documented progressive disease as detailed in the protocol

Exclusion Criteria:

  • Patient has received previous treatment with a PI3K and/or AKT and/or mTOR inhibitor (mTOR inhibitor is allowed in expansion cohorts where patients should have areceived a prior mTOR inhibitor)
  • Known intolerance or hypersensitivity to Everolimus or other rapamycin analogs
  • Patient with primary central nervous system (CNS) tumor or CNS tumor involvement as detailed in the protocol
  • Patient with diabetes mellitus, or documented steroid-induced diabetes mellitus
  • Patient has a history of another malignancy within 2 years prior to starting study treatment as described in the protocol
  • Patient who has not recovered to grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy as detailed in the protocol
  • Patient who has had systemic therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to starting study treatment
  • Patient who has received radiotherapy ≤ 4 weeks prior to starting study drugs, with exception of palliative radiotherapy (≤ 2 weeks prior to starting study drugs), who has not recovered from side effects of such therapy to baseline or Grade ≤ 1 and/or from whom ≥ 30% of the bone marrow was irradiated
  • Patient who has undergone major surgery ≤ 4 weeks prior to starting study treatment or who has not recovered from side effects of such procedure
  • Patient has a clinically significant cardiac disease or impaired cardiac function or any severe and/or uncontrolled medical conditions as detailed in the protocol
  • Patient who is currently receiving medication with a known risk of prolonging the QT interval or inducing Torsades de Pointes (TdP) and the treatment cannot either be discontinued or switched to a different medication prior to starting study drug treatment
  • Patient who has participated in a prior investigational study within 30 days prior to enrollment as described in the protocol
  • Patient who is currently receiving treatment with drugs known to be moderate or strong inhibitors or inducers of isoenzymes CYP34A or CYP2C8 as described in the protocol. Switching to a different medication prior to start of treatment is allowed
  • Patient with impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral alpelisib, everolimus, exemestane
  • Patient with known positive serology for human immunodeficiency virus
  • Patients who have received live attenuated vaccines within 1 week of start of study drug and during the study as specified in the protocol.
  • Pregnant or nursing (lactating) woman as detailed in the protocol.
  • Patient who does not apply highly effective contraception during the study and through the duration as defined in the protocol
  • Patients in the mTOR inhibitor-pretreated cohorts: all of above first 19 criteria plus have discontinued prior mTOR inhibitor therapy due to non-tolerable toxicity
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02077933

Contacts
Contact: Novartis Pharmaceuticals 1-888-669-6682
Contact: Novartis Pharmaceuticals

Locations
United States, Arkansas
Highlands Oncology Group Dept of Highlands Oncology Grp Recruiting
Fayetteville, Arkansas, United States, 72703
Contact: Tia Hesington    479-872-8130    thesington@hogonc.com   
Principal Investigator: Joseph T. Beck         
United States, New York
Memorial Sloan Kettering Cancer Center SC - BYL719Z2102 Recruiting
New York, New York, United States, 10065
Contact: Pamela Akametalu    646-888-4425    akametap@mskcc.org   
Principal Investigator: Anna G. Varghese         
France
Novartis Investigative Site Recruiting
Bordeaux, France, 33076
Novartis Investigative Site Recruiting
Bordeaux Cedex, France, 33075
Novartis Investigative Site Recruiting
Villejuif Cedex, France, 94805
Germany
Novartis Investigative Site Recruiting
Berlin, Germany, 12203
Novartis Investigative Site Recruiting
Essen, Germany, 45147
Novartis Investigative Site Recruiting
Hannover, Germany, 30625
Hong Kong
Novartis Investigative Site Recruiting
Hong Kong, Hong Kong
Hungary
Novartis Investigative Site Recruiting
Budapest, Hungary, H-1077
Italy
Novartis Investigative Site Recruiting
Ancona, AN, Italy, 60126
Novartis Investigative Site Recruiting
Milano, MI, Italy, 20141
Novartis Investigative Site Recruiting
Modena, MO, Italy, 41100
Novartis Investigative Site Recruiting
Verona, VR, Italy, 37126
Netherlands
Novartis Investigative Site Recruiting
Amsterdam, Netherlands, 1066 CX
Novartis Investigative Site Recruiting
Utrecht, Netherlands, 3584CX
Spain
Novartis Investigative Site Recruiting
Madrid, Spain, 28007
Novartis Investigative Site Recruiting
Madrid, Spain, 28034
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT02077933     History of Changes
Other Study ID Numbers: CBYL719Z2102 
Study First Received: February 28, 2014
Last Updated: January 20, 2016
Health Authority: France: L'Agence nationale de sécurité du médicament et des produits de santé (ANSM)
Germany: Federal Institute for Drugs and Medical Devices
Hong Kong: Department of Health
Hungary: National Institute of Pharmacy
Italy: The Italian Medicines Agency
Netherlands: Medicines Evaluation Board (MEB)
Spain: Spanish Agency of Medicines
United Kingdom: Medicines and Healthcare Products Regulatory Agency
United States: Food and Drug Administration

Keywords provided by Novartis:
Solid tumors,
renal cell carcinoma,
pancreatic neuroendocrine tumors,
breast cancer,
PI3K inhibitor,
BYL719,
alpelisib
everolimus,
exemestane

Additional relevant MeSH terms:
Adenoma, Islet Cell
Breast Neoplasms
Carcinoid Tumor
Carcinoma, Renal Cell
Kidney Neoplasms
Neoplasms
Neuroendocrine Tumors
Adenocarcinoma
Adenoma
Breast Diseases
Carcinoma
Digestive System Diseases
Digestive System Neoplasms
Endocrine Gland Neoplasms
Endocrine System Diseases
Kidney Diseases
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Germ Cell and Embryonal
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Neuroectodermal Tumors
Pancreatic Diseases
Pancreatic Neoplasms
Skin Diseases
Urogenital Neoplasms
Urologic Diseases
Urologic Neoplasms
Everolimus
Exemestane

ClinicalTrials.gov processed this record on April 27, 2016